[1,2-Dihydro-4(5)-acyl-2-oxo-2H-imidazol-4(5)-yl] methyl nitrates

ABSTRACT

1,3-Dihydro-2H-imidazol-2-ones having 5-acyl and 4-oxymethyl substituents, are useful as cardiotonics, antihypertensives and antithrombotic agents. The compounds are obtained by the reaction of an appropriate alcohol or a silver salt with a substituted 4-bromomethyl-1,3-dihydro-2H-imidazol-2-one.

The present application is a continuation-in-part of application Ser.No. 260,448, filed May 4, 1981, now abandoned.

The present invention relates to imidazoles having an acyl and anoxymethyl substituent at the 4- and 5-positions. More particularly, itrelates to compounds having the following general formula: ##STR1##wherein R is hydrogen, lower alkyl of 1-4 C, lower alkanoyl of 2-4 C, orbenzoyl; R¹ is lower alkyl of 1-4 C, phenyl, halophenyl, methylphenyl,methoxyphenyl, methylsulfonylphenyl, dimethylaminophenyl,dimethoxyphenyl, 3,4-methylenedioxyphenyl, 2-furyl, 2-thienyl orpyridyl; R² is hydrogen or lower alkyl of 1-4 C; and R³ is lower alkylof 1-4 C, lower alkanoyl of 2-4 C or nitro.

Examples of the lower alkyl groups referred to above are methyl, ethyl,propyl, isopropyl and butyl. The lower alkanoyl groups referred to abovecontain 2 to 4 carbon atoms and can be exemplified by acetyl, propionyland butyryl. Examples of the halophenyl groups referred to above includefluorophenyl, chlorophenyl and bromophenyl.

Within the scope of the invention are compounds of the formula: ##STR2##wherein R is hydrogen, lower alkanoyl of 2-4 C, or benzoyl; R¹ is loweralkyl of 1-4 C, phenyl, halophenyl, methylphenyl, methoxyphenyl,methylsulfonylphenyl, dimethylaminophenyl, dimethoxyphenyl,3,4-methylenedioxyphenyl, 2-furyl, 2-thienyl or pyridyl.

In addition, within the scope of the invention are nitrate compounds ofthe formula above wherein R is hydrogen, lower alkanoyl of 2-4 C, orbenzoyl; R¹ is phenyl, halophenyl, methylphenyl, methoxyphenyl,methylsulfonylphenyl, dimethylaminophenyl, dimethoxyphenyl or3,4-methylenedioxyphenyl.

Where R is hydrogen in the compounds of the present invention, severaltautomeric forms of the compounds are possible as follows: ##STR3##wherein the various groups are as defined earlier. These tautomers areacidic and can react with strong bases to form pharmaceuticallyacceptable salts of the following formulas: ##STR4## wherein the variousgroups are defined as above and M is a pharmaceutically acceptablealkali metal such as sodium or potassium. Throughout this disclosure,the term imidazol-2-one shall be taken to mean any of the tautomers orthe tautomer salts as set forth above.

As examples of compounds of the present invention are the following:

4-Benzoyl-1,3-dihydro-5-(ethoxymethyl)-2H-imidazol-2-one.

4-Propionyl-1,3-dihydro-5-(ethoxymethyl)-2H-imidazol-2-one.

5-(Propionyloxymethyl)-1,3-dihydro-4-(4-methoxybenzoyl)-2H-imidazol-2-one.

5-(Butyryloxymethyl)-1,3-dihydro-4-(4-methoxybenzoyl)-2H-imidazol-2-one.

4-(3-Pyridylcarbonyl)-5-(butoxymethyl)-1,3-dihydro-2H-imidazol-2-one.

1,3-Dihydro-4-(4-methoxybenzoyl)-5-(1-methoxethyl)-2H-imidazol-2-one.

1,3-Dipropionyl-1,3-dihydro-4-(4-methoxybenzoyl)-5-(ethoxymethyl)-2H-imidazol-2-one.

1,3-Dibenzoyl-1,3-dihydro-4-(4-methoxybenzoyl)-5-(ethoxymethyl)-2H-imidazol-2-one.

1,3-Dihydro-1,3-diethyl-4-(4-methoxybenzoyl)-5-(ethoxymethyl)-2H-imidazol-2-one.

[1,3-Dimethyl-4-(4-methoxybenzoyl)-1,3-dihydro-2-oxo-2H-imidazol-5-yl]methylnitrate.

(1,3-Diacetyl-4-benzoyl-1,3-dihydro-2-oxo-2H-imidazol-5-yl)methylnitrate.

[1,3-Diacetyl-4-(4-fluorobenzoyl)-1,3-dihydro-2-oxo-2H-imidazol-5-yl]methylnitrate.

[1,3-Diacetyl-4-(4-pyridinecarbonyl)-1,3-dihydro-2-oxo-2H-imidazol-5-yl]methylnitrate.

[1,3-Diacetyl-4-(2-pyridinecarbonyl)-1,3-dihydro-2-oxo-2H-imidazol-5-yl]methylnitrate.

The compounds of the present invention are prepared by the brominationof a 1,3-diacetyl imidazolone such as a compounds of the formula:##STR5## wherein Z is hydrogen to give the compound wherein Z is Br. Thereaction is carried out using N-bromosuccinimide in the presence of afree radical initiator such as benzoyl peroxide in an appropriatesolvent such as carbon tetrachloride. The specific diacetyl startingmaterials are obtained from the corresponding 1,3-unsubstitutedimidazolone by acetylation with acetyl chloride or acetic anhydride andthe unsubstituted imidazolones used are prepared in Belgian Pat. No.883,856 or they can be prepared by the same general procedures describedin the patent.

The bromomethyl compounds obtained above can be treated with hydrobromicacid in acetic acid to remove one or both of the N-acetyl groups. Toobtain the compounds in which R³ is lower alkyl, the resultingimidazolone is then treated with the appropriate alcohol; to obtain thecompounds in which R³ is lower alkanoyl or nitro, the bromomethylimidazolone is treated, respectively, with the silver salt of anappropriate alkanoic acid or silver nitrate. If the starting materialcontains N-acyl substitution, such groups can be treated with acid toremove the groups when R³ is lower alkyl or lower alkanoyl or an aminecan be used when R³ is nitro. Alternatively, the compounds in which R ishydrogen can be converted to compounds in which R is lower alkanoyl orbenzoyl by reaction of the compounds in which R represents hydrogen withan excess of the appropriate acid anhydride or acid chloride.

The compounds of the present invention can be used as anti-thrombotics.They affect the coagulation of blood by preventing the aggregation ofblood platelets, which play a dominant role in thrombotic conditionsboth in the initial event and at the occlusive stage. Arterialthrombosis, particularly in arteries supplying the heart muscle andbrain, is a leading cause of death and disability. The compounds of thepresent invention wherein R³ is nitro and R' is other than alkyl canalso be used in the treatment of hypertension including primary oressential hypertension, hormonally induced hypertension, renalhypertension and chemically induced hypertension. In addition, thecompounds of the present invention in which R³ is lower alkyl or loweralkanoyl can also be used in the treatment of cardiac failure includingcongestive heart failure, backward heart failure, forward heart failure,left ventricular heart failure, or right ventricular heart failure or inthe treatment of any other condition which requires the strengthening ofheart action with a cardiotonic.

Antihypertensive activity for the indicated nitro compounds wasdemonstrated using groups of 12 spontaneously hypertensive rats. Bloodpressure was measured by a pressure cuff occluder around the base of thetails of the rats. The blood pressure was determined in the animals,test compound was administered orally in a vehicle at a dose of 50 mg/kgand blood pressure was measured again at 1, 2, 3, 4 and 24 hours afteradministration of the test compound. The difference in blood pressureobserved was analyzed to establish if it was statistically significant.The vehicle used in administering the test compound did not have asignificant effect on blood pressure when used alone.

Cardiotonic activity for the compounds of the present invention whereinR³ is lower alkyl or lower alkanoyl was demonstrated by the followingprocedure. A Walton-Brodie strain gage arch was surgically implanted onthe heart of anesthetized dogs to measure cardiac contractile force.After the vital signs of the animal were stable for 10 minutes, testcompound was administered intravenously starting at a dose of 0.3 mg/kgand continuing with higher doses of 1, 3 and 10 mg/kg if no effect isobserved. Active compounds, such as compounds of the present invention,which increase cardiac contractile force measured in this way exert atrue positive inotropic effect, or a cardiotonic effect.

Antithrombotic activity for the present compounds is demonstrated by thefollowing procedure. When adenosine diphosphate is added to citratedplatelet rich human plasma, a typical aggregation of blood plateletsoccurs. Antithrombotic activity is determined by adding a test compoundto the citrated platelet rich human plasma in concentrations of 3, 10,30 and 100 ug/ml and subsequently adding adenosine diphosphate andobserving the extent of inhibition of aggregation of blood platelets.

The compounds may be administered in various manners to achieve thedesired effect. The compounds may be administered alone or in the formof pharmaceutical preparations to the patient being treated eitherorally or parenterally, that is, intravenously or intramuscularly. Theamount of compound administered will vary with the severity of thedisorder involved and the mode of administration. For oraladministration the antihypertensively effective amount of compound isfrom about 1.0 mg/kg (milligrams per kilograms) of patient body weightper day to about 100 mg/kg of patient body weight per day and preferablyfrom about 3.0 mg/kg of patient body weight per day to about 60 mg/kg ofpatient body weight per day.

For parenteral administration the antihypertensively effective amount ofcompound is from about 0.1 mg/kg of patient body weight per day up toabout 50 mg/kg of patient body weight per day and preferably from about1.0 mg/kg of patient body weight per day up to about 20.0 mg/kg ofpatient body weight per day. For oral or parenteral administration thecardiotonically effective amount of compound is from about 0.1 mg/kg ofpatient body weight per day up to about 50 mg/kg of patient body weightper day and preferably from about 1.0 mg/kg of patient body weight perday up to about 20.0 mg/kg of patient body weight per day. For oral orparenteral administration the anticoagulant effective amount of compoundis from about 0.1 mg/kg of patient body weight per day up to about 100mg/kg of patient body weight per day and preferably from about 0.1 mg/kgof patient body weight per day up to about 50 mg/kg of patient bodyweight per day.

For oral administration a unit dosage may contain, for example, from 100to 500 mg of the active ingredient. For parenteral administration a unitdosage may contain, for example, from 5 to 10 mg of the activeingredient. Repetitive daily administration of the compounds may bedesired and will vary with the condition of the patient and the mode ofadministration.

As used herein the term patient is taken to mean a warm blooded animal,for example, birds, such as chickens and turkeys, and mammals, such asprimates, humans, sheep, horses, bovine cows and bulls, pigs, dogs,cats, rats and mice.

For oral administration the compounds can be formulated into solid orliquid preparations such as capsules, pills, tablets, troches, powders,solutions, suspensions or emulsions. The solid unit dosage forms can bea capsule which can be of the ordinary gelatin type containing, forexample, lubricants and inert filler, such as lactose, sucrose andcornstarch. In another embodiment, the compounds of the invention can betableted with conventional tablet bases such as lactose, sucrose andcornstarch in combination with binders, such as acacia, cornstarch orgelatin, disintegrating agents such as potato starch or alginic acid,and a lubricant such as stearic acid or magnesium stearate.

For parenteral administration the compounds may be administered asinjectable dosages of a solution or suspension of the compound in aphysiologically acceptable diluent with a pharmaceutical carrier whichcan be a sterile liquid such as water and oils with or without theaddition of a surfactant and other pharmaceutically acceptableadjuvants. Illustrative of oils which can be employed in thesepreparations are those of petroleum, animal, vegetable or syntheticorigin, for example, peanut oil, soybean oil and mineral oil. Ingeneral, water, saline, aqueous dextrose and related sugar solutions,ethanol and glycols such as propylene glycol or polyethylene glycol and2-pyrrolidone can be used as liquid carriers for injectable solutions.Particularly preferred are combinations of the above carriers such asaqueous ethanol or propylene glycol-aqueous ethanol at alkaline pH.

The compounds can be administered in the form of a depot injection orimplant preparation which may be formulated in such a manner as topermit a sustained release of the active ingredient. The activeingredient can be compressed into pellets or small cylinders andimplanted subcutaneously or intramuscularly as depot injections orimplants. Implants may employ inert materials such as biodegradablepolymers or synthetic silicones, for example, Silastic, silicone rubbermanufactured by the Dow-Corning Corporation.

Following are illustrative pharmaceutical formulations which may beemployed in practicing the present invention:

    ______________________________________                           Per Tablet    ______________________________________    Preparation of a Tablet Formulation    (a)    1,3-Dihydro-4-(methoxybenzoyl)-5-                                 100      mg           (methoxymethyl)-2 --H--imidazol-2-one    (b)    Cornstarch            15       mg    (c)    Lactose               33.5     mg    (d)    Magnesium stearate    1.5      mg    Preparation of a Parenteral Formulation    (a)    1,3-Dihydro-4-(4-methoxybenzoyl)-5-                                 0.100    g           (methoxymethyl)-2 --H--imidazol-2-one    (b)    Sodium hydroxide      0.025    g    (c)    Ethanol               1.516    g    (d)    Propylene glycol      8.264    g    (e)    Water for injection qs ad                                 20.0     ml    ______________________________________

The following examples are set forth to illustrate the preparation ofcompounds employed in the present invention but should not be construedas limiting it in any way.

EXAMPLE 1

To a stirred mixture of 98.1 g (1 mole) of1,3-dihydro-4-methyl-2H-imidazol-2-one, 266.7 g (2 moles) of anhydrousaluminum chloride and 500 ml of nitrobenzene there is added dropwiseover 10 minutes, 158.6 g (1 mole) of p-fluorobenzoyl chloride. Themixture is stirred at 60°-65° C. for 6 hours, then poured onto 2 kg ofice. The precipitate which forms is separated by filtration, washed withdiethyl ether and water and recrystallized from dimethylformamide togive 1,3-dihydro-4-(4-fluorobenzoyl)-5-methyl-2H-imidazol-2-one meltingat about 289°-292° C.

If the above procedure is repeated using1,3-dihydro-4-methyl-2H-imidazol-2-one and the appropriate acidchloride, the following compounds are obtained:

1,3-Dihydro-4-methyl-5-[4-(methylsulfonyl)benzoyl]-2H-imidazol-2-one.

1,3-Dihydro-4-(4-methoxybenzoyl)-5-methyl-2H-imidazol-2-one melting atabout 257°-258° C. (dec.) after recrystallization fromisopropanol-water.

4-Benzoyl-1,3-dihydro-5-methylimidazol-2-one melting at about 250°-254°C.

1,3-Dihydro-4-methyl-5-(2-thiophenecarbonyl)-2H-imidazol-2-one meltingat about 212°-215° C. In this case, the material obtained after pouringthe mixture onto ice water is extracted into ethyl acetate and the ethylacetate solution is dried and the solvent is evaporated.

1,3-Dihydro-4-(3,4-dimethoxybenzoyl)-5-methyl-2H-imidazol-2-one meltingat about 257°-259° C. after recrystallization twice from ethanol-water.

1,3-Dihydro-4-(2-furoyl)-5-methyl-2H-imidazol-2-one melting at about214°-216° C. after recrystallization twice from methanol.

1,3-Dihydro-4-(3,4-methylenedioxybenzoyl)-5-methyl-2H-imidazol-2-onemelting at about 293°-296° C. (dec).

1,3-Dihydro-5-ethyl-4-(4-methoxybenzoyl)-2H-imidazol-2-one melting atabout 132° C. (dec).

1,3-Dihydro-5-methyl-4-(4-pyridinecarbonyl)-2H-imidazol-2-one melting atabout 296° C. (dec).

4-Acetyl-1,3-dihydro-5-methylimidazol-2-one melting at about 314°-316°C.

EXAMPLE 2

The sodium salt of1,3-dihydro-4-(4-methoxybenzoyl)-5-methyl-2H-imidazol-2-one is preparedfrom 7.0 g of1,3-dihydro-4-(4-methoxybenzoyl)-5-methyl-2H-imidazol-2-one in 100 ml ofmethanol with the addition of 1.6 g of sodium methoxide. A mixture isprepared from 8.0 g of this sodium salt, 120 ml of dimethylsulfoxide,15.2 g of powdered sodium hydroxide, and 19.5 g of methyl iodide. Thismixture is stirred at room temperature for 60 minutes and then pouredinto 800 ml of water. The resulting mixture is then extracted withmethylene chloride and the solvent is evaporated from the extract togive a solid. This is crystallized from ether to give1,3-dihydro-4-(4-methoxybenzoyl)-1,3,5-trimethyl-2H-imidazol-2-onemelting at about 109°-111° C.

EXAMPLE 3

To 2.0 g of 1,3-dihydro-4-(4-methoxybenzoyl)-5-methyl-2H-imidazol-2-onein 30 ml of dimethyl sulfoxide is added 0.29 g of sodium hydride and1.22 g of methyl iodide. The mixture is stirred at 22° C. for 30minutes, poured in methylene chloride, and washed with water. Themethylene chloride solution is dried and the solvent is evaporated toleave an oil which is triturated with chloroform to give a solid. Thissolid is recrystallized from methanol to give 1,3-dihydro-(1 or3),5-dimethyl-4-(4-methoxybenzoyl)-2H-imidazol-2-one melting at about225°-228° C.

EXAMPLE 4

A mixture of 46.4 g of1,3-dihydro-4-(4-methoxybenzoyl)-5-methyl-2H-imidazol-2-one and 200 mlof acetic anhydride is refluxed for 2 hours. The mixture is distilled toremove 100 ml of acetic anhydride and acetic acid; this is replaced byfresh acetic anhydride and refluxing is resumed. After a total of 4hours of reflux, excess acetic anhydride is evaporated under reducedpressure and the resulting residue is crystallized from ethanol to give1,3-diacetyl-1,3-dihydro-4-(4-methoxybenzoyl)-5-methyl-2H-imidazol-2-onemelting at about 123°-125° C.

If the above procedure is repeated using acetic anhydride and theappropriate substituted 1,3-dihydro-2H-imidazol-2-one, the followingcompounds are obtained:

4-Benzoyl-1,3-diacetyl-1,3-dihydro-5-methyl-2H-imidazol-2-one melting atabout 120°-122° C.

1,3-Diacetyl-1,3-dihydro-4-(4-fluorobenzoyl)-5-methyl-2H-imidazol-2-onemelting at about 102°-103° C.

1,3-Diacetyl-1,3-dihydro-4-(4-dimethylaminobenzoyl)-5-methyl-2H-imidazol-2-onemelting at about 183°-184° C.

1,3-Dihydro-1,3,4-triacetyl-5-methyl-2H-imidazol-2-one melting at about73°-75° C.

1,3-Diacetyl-1,3-dihydro-4-(3,4-dimethoxybenzoyl)-5-methyl-2H-imidazol-2-one.

1,3-Diacetyl-1,3-dihydro-4-(3,4-methylenedioxybenzoyl)-5-methyl-2H-imidazol-2-one.

1,3-Diacetyl-1,3-dihydro-4-(4-methylsulfonylbenzoyl)-5-methyl-2H-imidazol-2-one.

1,3-Diacetyl-1,3-dihydro-4-(2-furoyl)-5-methyl-2H-imidazol-2-one.

1,3-Diacetyl-1,3-dihydro-4-(2-thiophenecarbonyl)-5-methyl-2H-imidazol-2-one

1,3-Diacetyl-1,3-dihydro-5-methyl-4-(4-pyridinecarbonyl)-2H-imidazol-2-one.

1,3-Diacetyl-1,3-dihydro-5-ethyl-4-(4-methoxybenzoyl)-2H-imidazol-2-one.

EXAMPLE 5

A mixture of 55.5 g (0.176 mole) of1,3-diacetyl-1,3-dihydro-4-(4-methoxybenzoyl)-5-methyl-2H-imidazol-2-one,37.4 g (0.210 mole) of N-bromosuccinimide and about 100 mg of benzoylperoxide in 500 ml of carbon tetrachloride is stirred at refluxtemperature for 4 hours. The mixture is then cooled and filtered toremove the succinimide which formed. The solvent is evaporated from thefiltrate and the resulting residue is crystallized from a mixture of 300ml of ethyl acetate and 300 ml of hexane to give5-(bromomethyl)-1,3-diacetyl-1,3-dihydro-4-(4-methoxybenzoyl)-2H-imidazol-2-onemelting at about 135°-136° C.

If the above procedure is repeated using N-bromosuccinimide and theappropriate substituted 1,3-diacetyl-1,3-dihydro-2H-imidazol-2-one, thefollowing compounds are obtained:

5-(Bromomethyl)-1,3-diacetyl-1,3-dihydro-4-(4-fluorobenzoyl)-2H-imidazol-2-onemelting at about 113°-120° C.

5-(Bromomethyl)-1,3-dihydro-1,3,4-triacetyl-2H-imidazol-2-one melting atabout 88°-90° C.

4-Benzoyl-5-(bromomethyl)-1,3-diacetyl-1,3-dihydro-2H-imidazol-2-one.

5-(Bromomethyl)-1,3-diacetyl-1,3-dihydro-4-(3,4-dimethoxybenzoyl)-2H-imidazol-2-one.

5-(Bromomethyl)-1,3-diacetyl-1,3-dihydro-4-(3,4-methylenedioxybenzoyl)-2H-imidazol-2-one.

5-(Bromomethyl)-1,3-diacetyl-1,3-dihydro-4-(4-methylsulfonylbenzoyl)-2H-imidazol-2-one.

5-(Bromomethyl)-1,3-diacetyl-1,3-dihydro-4-(4-dimethylaminobenzoyl)-2H-imidazol-2-one.

5-(Bromomethyl)-1,3-diacetyl-1,3-dihydro-4-(2-furoyl)-2H-imidazol-2-one.

5-(Bromomethyl)-1,3-diacetyl-1,3-dihydro-4-(2-thiophenecarbonyl)-2H-imidazol-2-one.

5-(Bromomethyl)-1,3-diacetyl-1,3-dihydro-4-(4-pyridinecarbonyl)-2H-imidazol-2-one.

5-(1-Bromoethyl)-1,3-diacetyl-1,3-dihydro-4-(4-methoxybenzoyl)-2H-imidazol-2-one.

5-(Bromomethyl)-1,3-dihydro-1,3-dimethyl-4-(4-methoxybenzoyl)-2H-imidazol-2-one.

5-(Bromomethyl)-1,3-dihydro-4-(4-methoxybenzoyl)-(1 or3)-methyl-2H-imidazol-2-one.

EXAMPLE 6

A mixture of 50 g of5-(bromomethyl)-1,3-diacetyl-1,3-dihydro-4-(4-methoxybenzoyl)-2H-imidazol-2-onein 75 ml of 30% hydrobromic acid in acetic acid and 150 ml of aceticacid is heated to 80° C. on a steam bath and allowed to stand for 2hours. The mixture is then evaporated to dryness under reduced pressureand the residue is crystallized from acetic acid and then dried in vacuoat 80° C. over potassium hydroxide. This gives5-(bromomethyl)-1,3-dihydro-4-(4-methoxybenzoyl)-2H-imidazol-2-onemelting at about 205°-207° C. with decomposition.

If the above procedure is repeated using the appropriate5-(bromomethyl)-1,3-diacetyl-1,3-dihydro-2H-imidazol-2-one, thefollowing products are obtained:

5-(Bromomethyl)-1,3-dihydro-4-(4-fluorobenzoyl)-2H-imidazol-2-onemelting at greater than 300° C. with decomposition.

4-Benzoyl-5-(bromomethyl)-1,3-dihydro-2H-imidazol-2-one.

5-(Bromomethyl)-1,3-dihydro-4-(3,4-dimethoxybenzoyl)-2H-imidazol-2-one.

5-(Bromomethyl)-1,3-dihydro-4-(3,4-methylenedioxybenzoyl)-2H-imidazol-2-one.

5-(Bromomethyl)-1,3-dihydro-4-(4-methylsulfonylbenzoyl)-2H-imidazol-2-one.

5-(Bromomethyl)-1,3-dihydro-4-(4-dimethylaminobenzoyl)-2H-imidazol-2-one.

5-(Bromomethyl)-1,3-dihydro-4-(2-furoyl)-2H-imidazol-2-one.

5-(Bromomethyl)-1,3-dihydro-4-(2-thiophenecarbonyl)-2H-imidazol-2-one.

4-Acetyl-5-(bromomethyl)-1,3-dihydro-2H-imidazol-2-one.

5-(Bromomethyl)-1,3-dihydro-4-(4-pyridinecarbonyl)-2H-imidazol-2-one.

5-(1-Bromoethyl)-1,3-dihydro-4-(4-methoxybenzoyl)-2H-imidazol-2-one.

EXAMPLE 7

A solution of 4.0 g of5-(bromomethyl)-1,3-diacetyl-1,3-dihydro-4-(4-methoxybenzoyl)-2H-imidazol-2-onein 50 ml of dry tetrahydrofuran is cooled to -78° C. under argon, 1.0 mlof dry methanol is added by syringe, and the solution is allowed to warmto 25° C. over 1.5 hours. Concentrated hydrobromic acid (1 ml) is thenadded and the mixture is stirred at 25° C. overnight. The solvent isthen evaporated and the residual solid is recrystallized twice from amixture of methanol and water to give1,3-dihydro-4-(4-methoxybenzoyl)-5-(methoxymethyl)-2H-imidazol-2-onemelting at about 211°-212° C. with decomposition. This compound has thefollowing structural formula: ##STR6##

EXAMPLE 8

If the procedure of Example 7 is repeated using5-(bromomethyl)-1,3-diacetyl-1,3-dihydro-4-(4-methoxybenzoyl)-2H-imidazol-2-oneand the appropriate alcohol, the following compounds are obtained:

1,3-Dihydro-4-(4-methoxybenzoyl)-5-(isopropoxymethyl)-2H-imidazol-2-one.

1,3-Dihydro-4-(4-methoxybenzoyl)-5-[(1-pentyloxy)-methyl]-2H-imidazol-2-one.

EXAMPLE 9

If the appropriate 4-substituted5-(bromoalkyl)-1,3-diacetyl-1,3-dihydro-2H-imidazol-2-one is reactedwith methanol according to the procedure described in Example 7, thefollowing compounds are obtained:

1,3-Dihydro-4-(4-fluorobenzoyl)-5-(methoxymethyl)-2H-imidazol-2-one.

4-Benzoyl-1,3-dihydro-5-(methoxymethyl)-2H-imidazol-2-one.

1,3-Dihydro-4-(3,4-dimethoxybenzoyl)-5-(methoxymethyl)-2H-imidazol-2-one.

1,3-Dihydro-5-(methoxymethyl)-4-(3,4-methylenedioxybenzoyl)-2H-imidazol-2-one.

1,3-Dihydro-5-(methoxymethyl)-4-(4-methylsulfonylbenzoyl)-2H-imidazol-2-one.

1,3-Dihydro-4-(4-dimethylaminobenzoyl)-5-(methoxymethyl)-2H-imidazol-2-one.

1,3-Dihydro-4-(4-methoxybenzoyl)-5-(methoxymethyl)-1,3-dimethyl-2H-imidazol-2-one.

1,3-Dihydro-4-(2-furoyl)-5-(methoxymethyl)-2H-imidazol-2-one.

1,3-Dihydro-5-(methoxymethyl)-4-(2-thiophenecarbonyl)-2H-imidazol-2-one.

1,3-Dihydro-5-(methoxymethyl)-4-(4-pyridinecarbonyl)-2H-imidazol-2-one.

1,3-Dihydro-5-(1-methoxyethyl)-4-(4-pyridinecarbonyl)-2H-imidazol-2-one.

4-Acetyl-1,3-dihydro-5-(methoxymethyl)-2H-imidazol-2-one.

EXAMPLE 10

5-(Bromomethyl)-1,3-dihydro-4-(4-methoxybenzoyl)-2H-imidazol-2-one (3.1g) is dissolved in 80 ml of acetic acid by warming on a steam bath. Thesolution obtained is allowed to cool to about 25°-45° C. and 1.7 g ofsilver acetate is added. The mixture is stirred at 25° C. for 16 hoursand the precipitate which forms (silver bromide) is removed byfiltration. The filtrate is concentrated to about 10 ml and a solidcrystallizes. This is separated by filtration and recrystallized fromacetic acid to give4-[(acetyloxy)methyl]-1,3-dihydro-5-(4-methoxybenzoyl)-2H-imidazol-2-onemelting at about 155°-162° C. This compound has the following structuralformula: ##STR7##

EXAMPLE 11

If the procedure of Example 10 is repeated using silver acetate and theappropriately substituted 5-(bromomethyl)-1,3-dihydro-2H-imidazol-2-one,the following compounds are obtained:

5-Acetyl-4-[(acetyloxy)methyl]-1,3-dihydro-2H-imidazol-2-one.

4-[(Acetyloxy)methyl]-1,3-dihydro-5-(2-thiophenecarbonyl)-2H-imidazol-2-one.

If the procedure of Example 11 is repeated using5-(bromomethyl)-1,3-dihydro-4-(4-methoxybenzoyl)-2H-imidazol-2-one,propionic acid and silver propionate, the product obtained is1,3-dihydro-5-(4-methoxybenzoyl)-4-[(propionyloxy)methyl]-2H-imidazol-2-one.

Similarly, if5-(bromomethyl)-1,3-dihydro-1,3-dimethyl-4-(4-methoxybenzoyl)-2H-imidazol-2-oneis reacted with silver acetate, the product obtained is4-[(acetyloxy)methyl]-1,3-dihydro-1,3-dimethyl-5-(4-methoxybenzoyl)-2H-imidazol-2-one.

EXAMPLE 12

To a solution of 6.8 g of silver nitrate in 40 ml of dry acetonitrile at0° C. is added, dropwise, over a period of 15 minutes, a solution of12.1 g of 1,3,4-triacetyl-5-(bromomethyl)-1,3-dihydro-2H-imidazol-2-one(in acetonitrile). The mixture is stirred at 0° C. for 45 minutes andthe precipitate which forms (silver bromide) is removed by filtration.The solvent is evaporated from the filtrate under reduced pressure andthe residue is partitioned between ethyl acetate and water. The ethylacetate phase is separated, washed with water and dried over magnesiumsulfate and the solvent is then evaporated. The residue is thenrecrystallized from a mixture of ethyl acetate and hexane and then fromethyl acetate alone to give(1,3,4-triacetyl-1,3-dihydro-2-oxo-2H-imidazol-5-yl)methyl nitratemelting at about 135°-136° C. with decomposition.

If the above procedure is repeated using5-(bromomethyl)-1,3-dihydro-4-(4-methoxybenzoyl)-2H-imidazol-2-one andthe silver nitrate in 200 ml of acetonitrile, the product obtained is[4-(4-methoxybenzoyl)-1,3-dihydro-2-oxo-2H-imidazol-5-yl]methyl nitrate.

If the above procedure is repeated using silver nitrate and5-(bromomethyl)-1,3-diacetyl-1,3-dihydro-4-(4-methoxybenzoyl)-2H-imidazol-2-one,the product obtained is[1,3-diacetyl-4-(4-methylbenzoyl)-1,3-dihydro-2-oxo-2H-imidazol-5-yl]methylnitrate melting at about 104°-104.5° C. This compound has the followingstructural formula: ##STR8##

EXAMPLE 13

To a cold solution (10° C.) of 1.9 g of[1,3-diacetyl-4-(4-methoxybenzoyl)-1,3-dihydro-2-oxo-2H-imidazol-5-yl]-methylnitrate in 30 ml of ethyl ether and 20 ml of ethyl acetate there isadded a solution of 470 mg of piperidine in 10 ml of ethyl ether and thesolution is stirred at 25° C. for 30 minutes. Water (30 ml) is added andthe precipitate which forms is separated and recrystallized twice fromethyl acetate to give[1-acetyl-1,3-dihydro-5-(4-methoxybenzoyl)-2-oxo-2H-imidazol-4-yl]methylnitrate melting at about 165°-166° C. with decomposition.

What is claimed is:
 1. A compound of the formula: ##STR9## wherein R ishydrogen, lower alkyl of 1-4 C, lower alkanoyl of 2-4 C, or benzoyl; R¹is lower alkyl of 1-4 C, phenyl, halophenyl, methylphenyl,methoxyphenyl, methylsulfonylphenyl, dimethylaminophenyl,dimethoxyphenyl, 3,4-methylenedioxyphenyl, 2-furyl, 2-thienyl orpyridyl.
 2. A compound according to claim 1 which has the formula:##STR10## wherein R is hydrogen, lower alkanoyl of 2-4 C, or benzoyl; R¹is lower alkyl of 1-4 C, phenyl, halophenyl, methylphenyl,methoxyphenyl, methylsulfonylphenyl, dimethylaminophenyl,dimethoxyphenyl, 3,4-methylenedioxyphenyl, 2-furyl, 2-thienyl orpyridyl.
 3. A compound according to claim 1 which has the formula:##STR11## wherein R is hydrogen, lower alkanoyl of 2-4 C, or benzoyl; R¹is phenyl, halophenyl, methylphenyl, methoxyphenyl,methylsulfonylphenyl, dimethylaminophenyl, dimethoxyphenyl or3,4-methylenedioxyphenyl.
 4. A compound according to claim 1 which is[1,3-diacetyl-4-(4-methoxybenzoyl)-1,3-dihydro-2-oxo-2H-imidazol-5-yl]methylnitrate.
 5. A compound according to claim 1 which is[1-acetyl-1,3-dihydro-5-(4-methoxybenzoyl)-2-oxo-2H-imidazol-4-yl]methylnitrate.